Immunochemical studies of genetically rapid and slow acetylator rabbits indicate that the INH acetylator polymorphism is due to qualitative rather than quantitative differences in liver N-acetyl transferase in the two acetylator phenotypes. Isoelectric focussing studies of the enzyme provide further support for this possibility. The latter studies combined with SDS electrophoresis also suggests that the polymorphic liver enzyme is polymeric. Probe studies have been carried out on three species of rodents, including the deer mouse, several inbred strains of the house mouse and several strains of rats to determine the suitability as genetic models for drug acetylator polymorphisms. Both the deer mouse and selected strains of the house mouse (A/J, C57BL/6J) appear to be acceptable for this purpose. A project to explore the interrelationships between genetic factors affecting drug N-acetylation and drug-induced autoimmune states in the latter has been initiated. A new radiotracer assay was developed and used for investigating whether various mutagenic and carcinogenic arylamines are polymorphic substrates like INH. In vitro studies with liver homogenates from rapid and slow acetylators of both acetylator phenotypes show that all arylamines tested to date including 2-napthylamine, Beta-naphthylamine, 2-aminofluorene, benzidine and 4,4' methylene-2-chloroaniline do resemble INH in this respect. The implications of these results with respect to individual susceptibility to carcinogenesis from such agents are considered. Polymorphonuclear leukocytes and lymphocytes obtained from rapid and slow INH acetylators are being studied for biochemical correlates with acetylator phenotype. Preliminary evidence suggests that the heat stability of drug acetylating N-acetyltransferase activity in the lymphocyte from rapid acetylator persons is somewhat less than the activity in the slow acetylator lymphocyte. This may be useful individual characteristic for studying the regulator factors governing N-acetyltransferase activity and possibly for improving acetylator phenotype procedures. Each of these areas will continue to be actively explored next year with the broad objectives of advancing our understanding of genetic factors affecting the human pharmacology of drugs and other foreign compounds which under N-acetylation prior to elimination from the body.